The Molecular Interplay of Tau and Motor Proteins on Microtubules
- 1UC Berkeley
Abstract
Tau is a microtubule (MT)-associated protein essential for neuronal cytoskeletal organization and intracellular transport, yet how tau physically regulates motor proteins remains elusive. Here, we integrate single-molecule imaging, cryo-electron microscopy, and molecular dynamics (MD) simulations to investigate the molecular mechanisms underlying tau-mediated inhibition of kinesin-1 and cytoplasmic dynein motility. We show that tau suppresses MT landing and triggers frequent pausing and premature detachment when motors encounter tau-enriched patches. Unexpectedly, tau impairs each motor using different mechanisms. Tau and kinesin-1 compete for the same surface on tubulin, precluding simultaneous binding to the same MT site. On the other hand, while dynein and tau can co-occupy the same tubulin, tau inhibits the transition of dynein into its high-affinity MT-binding state. Thus, tau can act as a physical or a conformational roadblock in a concentration-dependent manner, exerting distinct structural constraints on kinesin and dynein transport. These findings establish a structural framework for tau-mediated regulation of axonal transport.
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BibTeX
@misc{he2026molecular,
title = {{The Molecular Interplay of Tau and Motor Proteins on Microtubules}},
author = {Y. He and J. Peukes and M. Golcuk and A. Y. Jack and L. S. Ferro and R. Tan and M. Gur and E. Nogales and A. Yildiz},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.02.763819},
url = {https://www.biorxiv.org/content/10.64898/2026.11.02.763819v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - The Molecular Interplay of Tau and Motor Proteins on Microtubules
AU - Y. He
AU - J. Peukes
AU - M. Golcuk
AU - A. Y. Jack
AU - L. S. Ferro
AU - R. Tan
AU - M. Gur
AU - E. Nogales
AU - A. Yildiz
PY - 2026
DA - 2026/11/02
PB - bioRxiv
DO - 10.64898/2026.11.02.763819
UR - https://www.biorxiv.org/content/10.64898/2026.11.02.763819v1
AB - Tau is a microtubule (MT)-associated protein essential for neuronal cytoskeletal organization and intracellular transport, yet how tau physically regulates motor proteins remains elusive. Here, we integrate single-molecule imaging, cryo-electron microscopy, and molecular dynamics (MD) simulations to investigate the molecular mechanisms underlying tau-mediated inhibition of kinesin-1 and cytoplasmic dynein motility. We show that tau suppresses MT landing and triggers frequent pausing and premature detachment when motors encounter tau-enriched patches. Unexpectedly, tau impairs each motor using different mechanisms. Tau and kinesin-1 compete for the same surface on tubulin, precluding simultaneous binding to the same MT site. On the other hand, while dynein and tau can co-occupy the same tubulin, tau inhibits the transition of dynein into its high-affinity MT-binding state. Thus, tau can act as a physical or a conformational roadblock in a concentration-dependent manner, exerting distinct structural constraints on kinesin and dynein transport. These findings establish a structural framework for tau-mediated regulation of axonal transport.
ER -